Inhibition of human non-small cell lung tumors by a c-Met antisense/U6 expression plasmid strategy

Stabile, Laura P.; Lyker, Jennifer S.; Huang, Leaf; Siegfried, Jill M.

doi:10.1038/sj.gt.3302169

Cited by 42 publications

(24 citation statements)

References 64 publications

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“…In preclinical experiments, an antisense oligonucleotide sequence against the MET mRNA showed activity against NSCLC [204] and glioma [205] xenografts. Further investigations of this therapy are underway.…”

Section: Antisense Therapymentioning

confidence: 99%

Therapeutic targeting of receptor tyrosine kinases in lung cancer

Choong

Patrick

Salgia

2005

Expert Opinion on Therapeutic Targets

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Lung cancer is a difficult illness with a poor overall survival. Even though combination strategies with chemotherapy, radiation therapy and surgery have all been utilised, the overall outcome for this disease continues to be relatively disappointing. In order to make a difference in the treatment of lung cancer, novel therapeutics will have to be developed. Through basic biological studies, a number of receptor tyrosine kinases have been implicated in the pathogenesis and progression of lung cancer. In this review, the authors summarise the mechanisms of several major receptor tyrosine kinases in lung cancer, especially epidermal growth factor receptor, Her2/neu, MET, vascular endothelial growth factor and KIT. The biology associated with these receptors is described, and the various novel therapeutic inhibitory strategies that are ongoing in preclinical and clinical studies for lung cancer are detailed. Through understanding of receptor tyrosine kinases and the utilisation of specific inhibitors, it is hopeful that a dramatic impact will be made on the biology and therapy for lung cancer.

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Section: Antisense Therapymentioning

confidence: 99%

Therapeutic targeting of receptor tyrosine kinases in lung cancer

Choong

Patrick

Salgia

2005

Expert Opinion on Therapeutic Targets

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“…We have documented previously HGF-induced phosphorylation of c-Met and activation of phospho-MAPK in these NSCLC cells; this occurs rapidly (with 5 min using 50 ng/ml HGF; Stabile et al, 2004). To examine biological effects that may be downstream of this activation, we examined the molpharm.aspetjournals.org extent of COX-2 protein expression.…”

Section: Cox-2 Induction Mediated By Hgf Nsclc Cell Linesmentioning

confidence: 99%

Signaling Pathways Involved in Cyclooxygenase-2 Induction by Hepatocyte Growth Factor in Non–Small-Cell Lung Cancer

et al. 2007

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Many studies have suggested a role for the hepatocyte growth factor (HGF)/c-Met pathway in tumorigenesis. Some actions of HGF are believed to be mediated by cyclooxygenase-2 (COX-2), resulting in the production of prostaglandin E2 (PGE 2 ). We examined four c-Met-positive non-small-cell lung cancer (NSCLC) cell lines for effects of HGF on COX-2. HGF increased COX-2 protein expression 3-fold over basal levels. Induction of COX-2 occurred through both the extracellular signal-regulated kinase 1/2 and p38 pathways. HGF treatment caused activation of the activator protein-1, CCAAT/enhancer-binding protein, and cAMP response element-binding protein transcription factors, and COX-2 induction was blocked by actinomycin D. The half-life of COX-2 mRNA was also increased by HGF. HGF stimulation resulted in a 4-fold increase in PGE 2 secretion, and treatment of NSCLC cells with exogenous PGE 2 significantly increased cell proliferation. The addition of PGE 2 to NSCLC cells also led to rapid phosphorylation of c-Met in the absence of HGF, which was blocked by epidermal growth factor receptor (EGFR) inhibition. EGFR ligands were released in response to PGE 2 . This suggests that secretion of PGE 2 induced by HGF/c-Met pathway activation can further activate the c-Met pathway via EGFR in a reinforcing loop that is independent of HGF. HGF and PGE 2 each significantly stimulated invasion in NSCLC cells. Cells transiently transfected with c-Met antisense plasmid showed a significant decrease in HGF-or PGE 2 -induced invasion. PGE 2 -induced invasion was EGFR-dependent, confirming a link between PGE 2 , EGFR, and c-Met. Targeting of both the HGF/c-Met and PGE 2 pathways with a neutralizing antibody to HGF and celecoxib resulted in enhanced antiinvasion effects in response to HGF.Lung cancer is the number one cause of death from cancer in men and women in the United States and worldwide is also a major cause of cancer deaths. The 5-year survival rate for lung cancer has shown little improvement over the past 20 years. New therapies that target specific lung cancerrelated growth pathways are needed to make an impact on the course of this disease, which is still often diagnosed at late stages that do not respond well to current therapies. The recent experience with the inhibitor of EGFR, gefitinib, which showed limited therapeutic efficacy (Twombly, 2005), suggests that the success of targeted therapies in clinical use may require different approaches, such as use in selected sensitive patients, combination therapy against several targets, or use of drugs intermittently at high doses to induce apoptosis rather than continuously at low doses to impair cell division.Growth factors and their receptors are attractive targets for therapy because these signaling pathways control cell division and cell survival, two processes that are in imbalance in malignant cells. The literature has repeatedly demonstrated that many growth factor and oncogene signaling pathways overlap and interact with each other. This suggests that not only is...

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“…Dysregulation of Met signaling results in enhanced tumorigenicity and metastatic potential in engineered cells and in transgenic mice (25)(26)(27)(28). Conversely, inhibition of Met signaling using ribozymes, antisense RNA, anti-HGF antibodies, or an inhibitory fragment of HGF inhibits growth of tumor xenografts in mice (29)(30)(31)(32)(33)(34)(35).…”

Section: Introductionmentioning

confidence: 99%